Full text of "USPTO Patents Application 09634399"

See other formats

This Page Is Inserted by IFW Operations
and is not a part of the Official Record

BEST AVAILABLE IMAGES

Defective images within this document are accurate representations of
the ongmal documents submitted by the applicant.

Defects in the images may include (but are not hmited to):

• BLACK BORDERS

• TEXT CUT OFF AT TOP, BOTTOM OR SIDES

• FADED TEXT

• ILLEGBLE TEXT

• SKEWED/SLANTED IMAGES

• COLORED PHOTOS

• BLACK OR VERY BLACK AND WHITE DARK PHOTOS

• GRAY SCALE DOCUMENTS

IMAGES ARE BEST AVAILABLE COPY.

As rescanning documents will not correct images,
please do not report the images to the
image Problem Mailbox.

—

wo 97/03709

PCT/EP96/03033

[WPO/OMPI LOGO]

PCX WORLD INTELLECTUAL PROPERTY ORGANIZATION

International Bureau

INTERNATIONAL APPLICATION PUBLICHED UNDER THE PATENT COOPERATION TREATY (PCT)

(5 1 ) International Patent Classification^*

A61L 15/44, A61K 31/565, C07J 1/100 Al

(2/6/97)

(1 1) International Publication No. WO 97/03709
(43) International Publication Date: February 6, 1997

(21) International Application No.: PCT/EP96/03033

(22) International Application Date: July 6, 1996 (7/6/96)

(30) Priority Data:

195 26 789.3 July 17, 1995 (7/17/95) DE

196 13 698.9 April 1, 1996 (4/1/96) DE

(81) Designated Countries: AU, BR, CA, CN, CZ, FI,
HU, IL, JI, KR, MX, NO, NZ, PL, RU, SK, UA, US,
VN, European patents (AT, BE, CH, DE, DK, ES, FI,
FR, GB, GR, IE, IT, LU, MC, NL, PT, SE).

Published

with international research report.

(71) Applicant (for all designated countries except US):

SCHERING AKTIENGESELLSCHAFT (DE/DE);
D- 13342 Berlin (DE).

(72) Inventor; and

(75) Inventor/Applicant: (only for US): LIPP, Ralph [DE/DE];

Lenaer Strasse 8, D-10717 Berlin (DE). EWERS, Christian
[DE/DE]; Rheinsteinstrasse 68, D-10318 Berlin (DE).
GUNTHER, Clemens [DE/DE]; Gottschedstrasse 26, D-13357
Berlin (DE). RIEDEL, Jutta [DE/DE]; Flesburger Strasse 14,
D-10557 Berlin (DE). TAUBER, Uhich [DE/DE]; Ostender
Strasse 3, D-13353 Berlin (DE).

(54) Title: TRANSDERMAL APPLICATION AGENT CONTAINING ESTERS OF 3-KETODESOGESTREL
(57) Abstract

An agent for transdermal application characterized in that it contains esters of
13 -ethyl- 17B-hydroxy-l l-methylene-18,19-dinor-17?-pregn-4-ene-20yne-3-one with 1 to 20,carbon atoms in the
ester group, optionally in combination with 1 or 2 estrogens.

Translated by Tex Translation & Interpreting Services * 1518 Wabiut Street - Suite 1407, Philadelphia, PA USA

215-772-1820/fax 215-772-182

WO 97/03709

PCT/EP96/03033

FOR INFORMATION ONLY

Codes for the identification of PCT-Treaty Countries on the front page of the pubhcation that international applicants publish
according to the PCT

Armenian

United Kingdom

Mexico

Austria

Georgia

Niger

Australia

Guinea

Netherlands

Barbados

Greek

Norwegian

Belgium

Hungary

New Zealand

Burkina Faso

Ireland

Poland

Bulgaria

Italy

Portugal

Benin

Japan

Romanian

Brazil

Kenya

Russian Federation

Belarus

Kirghizstan

Sudan

Canada

FCP

Democratic People's Republic of Korea

Sweden

Central African Republic

ICR

Korean Republic

Singapore

Congo

Kazachstan

Slovinia

Switzerland

Lichtenstein

Slovakia

Ivory Coast

Sri Lanka

Senegal

Cameroon

Liberia

Swasiland

China

Lithuania

Chad

Czechoslovakia

Luxemburg

Togo

Czech Republic

Lapland

Tadschikistan

Germany

Monaco

Trinidad and Tobago

Denmark

Moldavian Republic

Ukraine

Iceland

Madagascar

Uganda

Spain

MaU

United States of America

Finland

Mongolia

Uzbekistan

France

Mauritania

Vietnam

Gabon

Malawi

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

21 5-772- 1820/fax 215-772-182

wo 97/03709

PCT/EP96/03033

AGENT FOR TRANSDERMAL APPLICATION CONTAINING ESTERS OF 3-KETODESOGESTREL

The invention concerns an agent for transdermal applications, which is characterized in that it
contains esters of

13-ethyl-17?-hydroxy-ll-methylene-18,19-dinor-17?-pregn-4-ene-20-yne-3-one with 1 to 20
carbon atoms in the ester group, optionally in combination with one or more estrogen(s).

These esters of 13-ethyl-17?-hydroxy-l 1 -methylene- 1 8, 19-dinor-17?-pregn-4-ene-20-yne-3 -one
are characterized by the generic formula

in which R is an acyl group with 1 to 20 carbon atoms.

In particular, the invention concerns such transdermal application agents containing esters of
13-ethyl-17?-hydroxy-l l-methylene-18,19-dinor-17?-pregn-4-ene-20-yne-3-one with 2 to 12
carbon atoms in the acyl group and especially agents containing alkanoyl esters of
13-ethyl-17?-hydroxy-l l-methylene-18,19-dinor-17?-pregn-4-ene-20-yne-3-one with 2 to 8
carbon atoms in the alkanoyl group. As, heretofore unknown, suitable esters of
1 3 -ethyl- 1 7?-hydroxy- 1 1 -methylene- 18,1 9-dinor-17?-pregn-4-ene-20-yne-3 -one being stressed
in particular are their acetates, their butyrates and preferably their hexanoates, which are likewise
the subject of the present invention and the production of which is described later.

13-EthyM7?-hydroxy-l l-methylene-18,19-dinor-17?-pregn-4-ene-20-yne-3-one itself is a
known substance with extraordinarily high gestagenic activity which in the form of its Pro-drug
13-ethyl-ll-methylene-18,19-dinor-17?-pregn-4-ene-17?-ol (J. Of Steroid Biochem., 14, 1981,
175 pp and Europ. J. Clin. Pharmakol., 15, 1979, 449 pp) in combination with estrogen effective

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

215-772-1820/fax 215-772-182

wo 97/03709

PCT/EP96/03033

compounds are used for producing oral application agents with conception prevention action
(Marvelon®).

It is now found surprisingly that the esters of

13-ethyl-17?-hydroxy-l l-methylene-18,19-dinor-17?-pregn-4-ene-20-yne-3-one, optionally in
combination with 1 or more estrogens can be used for producing a transdermal application agent
of active material, in some cases often better, than combination preparations, which themselves
contain esters of

1 3-ethyl-l 7?-hydroxy-l 1 -methylene- 18,1 9-dinor-l 7?-pregn-4-ene-20-yne-3-one.
By esterification of the 1 7p-position hydroxyl group of the esters of

13 -ethyl- 17?-hydroxy-l l-methylene-18,19-dinor-17?-pregn-4-ene-20-yne-3-one the physical
chemical properties of this substance are directed and bio-reversibly changed in the direction of a
Pro-drug- structure.

Upon comparing the skin penetration of the esters of

1 3 -ethyl- 1 7?-hydroxy- 1 1 -methylene- 18,1 9-dinor-l 7?-pregn-4-ene-20-yne-3-one with that of
their esters, thus the latter distinguishing itself in general by the clearly higher transdermal flow.
Above all, this is valuable in the performance of the ester in Matrix-Transdermal systems, like,
by way of example, Acrylate Type (as they are described later in Example 2).

The astonishingly high transdermal flow is clearly preferable to the surprisingly convenient
solubility, which, for the named esters of

13-ethyl-17?-hydroxy-ll-methylene-18,19-dinor-17?-pregn-4-ene-20-yne-3-one, is present in
the ordinary skin contact adhesive and their mixtures with co-solvents or penetration enhancers.
On the basis of this property now highly charged and stable matrix transdermal systems can be
produced with molecular dispersion distributing Pro-drugs. Self-active material charges, which
on a molecular basis are around the factor 15 higher than that comparable, even realizable, for
1 3-ethyl- 1 7?-hydroxy- 1 1 -methylene- 18,1 9-dinor- 1 7?-pregn-4-ene-20-yne-3 -one, lead to stable
systems. This is a distinct advantage over

1 3-ethyl- 1 7?-hydroxy- 1 1 -methylene- 18,1 9-dinor- 1 7?-pregn-4-ene-20-yne-3-one containing
systems which are previously known from WO94/04157, since the concentration level between
transdermal systems and the skin conclusively is responsible for the attainable height of the
transdermal flow.

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

215-772-1820/fax 215-772-182

wo 97/03709

PCT/EP96/03033

Thus, it is possible with help of agents according to the invention to obtain high uniform flows of
esters of l3-ethyl-17?-hydroxy-l 1 -methylene- 1 8, 19-dinor-17?-pregn-4-ene-20-yne-3 -one with
comparatively small transdermal systems.

It is already mentioned that the agent according to the invention, besides gestagens, can still
contain 1 or more estrogens.. By way of example, suitable estrogens are estradiol, estriol,
ethinylestradiol, mestranol, 14a,17a-ethanoestra-l,3,5(10)-tiene-3,17p-diol (WO 88/01275), 14
a,17a-ethanoestra-l,3,5(10)-tiene-3,16al7p-triol (WO 91/08219) and their esters (EP-A
163596), like estradioldipropionate, estradioldihexanoate and estradioldidecanoate. These
preparation combinations contain beside 1 or 2 gestodenestem preferably 1 to 3 , especially 1 to
2 estrogens.

The active material or active material mixture can be dissolved or suspended in suitable volatile
solvents and/or penetration-enhancing agents for producing pharmaceutical preparations,. The
solvents or suspensions obtained can be mixed with the customary additives, like matrix builders
and bactericides and, if necessary, after sterilization are emptied into dosing containers. On the
other hand, it is also possible to process these solutions or suspensions further to lotions and
salves by introducing emulsifiers and water. One can also - optionally with the addition of fuel
gas - produce Sprays that can be filled in customary dosing containers.

Suitable volatile solutions, by way of example, are low molecular weight alcohols, ketones or
low molecular weight carboxylic acid esters like ethanol, isopropanol, acetone or ethylacetate,
polar ether, like tetrahydrofuran, low molecular weight hydrocarbons, like n-hexane,
cyclohexane or benzene or halogen hydrocarbon as well, like dichloromethane,
trichloromethane, trichlorotrifluoroethane and trichrolofluoromethane. It is not necessary to
explain that mixtures of these solvents are also suitable.

Suitable penetration-enhancing agents are, by way of example, 1 or more valent alcohol(s), like
ethanol, 1,2-propandiol or benzyl alcohol , saturated and unsaturated fatty alcohols with 8 to 18
carbon atoms, like lauryl alcohol or cetyl alcohol, hydrocarbons, like mineral oils, saturated and
unsaturated fatty acids with 8 to 18 carbon atoms, like stearic acid or oleic acid, fatty acid esters
with up to 24 carbon atoms or dicarbolic acid diesters with up to 24 carbon atoms

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

215-772-1820/fax 215-772-182

I) < l> , f

wo 97/03709

PCT/EP96/03033

Fatty acid esters, which are suitable penetration-enhancing agents, by way of example, are such
as acetic acid, caproic acid, lauric acid, myristic acid, stearic acid, palmitic acid or oleic acid ,
like for example the methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters,
secondary-butyl esters, isobutyl esters, tertiary-butyl esters or monoglyceroesters of these acids.
Especially preferred esters are those of mystiric acid or oleic acid, like their methyl esters,
isopropyl esters or monogylceroesters. Suitable dicarboxylic acid esters are, by way of example,
diisopropyladipate, diisobutyladipate and diisopropylsebacate.

Additional penetration-enhancing agents are phosphate derivatives, like lecitin, terpenes, amides,
ketones, ureas and their derivatives or ethers like, for example, diethylene glycol monoethyl
ether or dimethyl isosorbit. There is no need to explain further that mixtures of these
penetration-enhancing agents are also suitable for producing agents according to the invention.

The concentration for the esters of

13-ethyl-17?-hydroxy-l 1 -methylene- 1 8, 19-dinor-17?-pregn-4-ene-20-yne-3-one in which the
active materials or active material mixtures are optimally suspended or dissolved in the solvent
agent, is usually 0.01 to 50 % by wt. Li the estrogens the concentration is normally dependent
upon the type active material used and the individual doses sought, in each case it must be done
by means of preliminary experiments by the specialist, like, for example, the determination of
the attainable active material concentration in the plasma, after selected dermal applications of
the system, according to the invention, are found. Here, in general, the active material
concentrations from 0,01 to 25 % by wt. of estrogen in the agent, according to the invention, are
also satisfactory. The weight relationship of the esters of

13-ethyl-17?-hydroxy-ll-methylene-18,19-dinor-17?-pregn-4-ene-20-yne-3-one to the 1 or more
estrogen(s) in the preparation combination is 5:1 to 1 : 10.

The daily dose therapeutic requirement of transdermal is indication-dependent and is in the range
of about 30-120?g of

13-ethyl-17?-hydroxy-l l-methylene-18,19-dinor-17?-pregn-4-ene-20-yne-3-one per day. The
esters of 13-ethyl-17?-hexanoyloxy-l 1 -methylene- 1 8, 19-dinor-17?-pregn-4-ene-20-yne-3-one
are equi-molar doses, in order to allow for the increase in molecular weight by the
Pro-drug-Structure. For example, the daily dose for the

13-ethyl-17?-hydroxy-l l-methylene-18,19-dinor-17?-pregn-4-ene-20-yne-3-one is about
40-150?g. Reference to a

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

21 5-772- 1820/fax 215-772-182

wo 97/03709

PCT/EP96/03033

transdermal system with a 20cm2 surface means that transdermal flows of up to 0.3?g of the
1 3 -ethyl- 1 7?-hexanolyoxy- 1 1 -methylene- 1 8, 1 9-dinor- 1 7?-pregn-4-ene-20-yne-3-one/cm2/h are
necessary. In in-vitro studies with known formulations it has been demonstrated that these were
clearly dropping excessively.

A very similar application with adjusted dosages of active materials or active material mixtures
can be obtained if the active material or the mixture is embedded in a transdermal therapeutic
system (TTS). Suitable transdermal therapeutic systems are those which one normally uses for
percutaneous applications of active materials (Yie W. Chien: "Transdermal Controlled Systemic
Medications", Marcel Dekker, Inc., New York and Basel 1987, Dr. Richard Baker: "Analysis of
Transdermal Drug Delivery Patents 1934 to 1984" and "Analysis of Recent Transdermal
Delivery Patents, 1984-1986 and Enhancers Membrane Technology & Research 1030 Hamilton
Court, Menlo Park, CA 94025 (415) 328-2228).

So, by way of example, one such transdermal therapeutic system can be used which consists of

a) an impermeable covering layer,

1 to 3 pasted to the covering layer, of 1 or more ester(s) of 13 -ethyl

- 1 7?-hydroxy- 1 1 -methylene- 18,1 9-dinor- 1 7?-pregn-4-ene-20-yne-3-one

containing optionally 1 or more estrogen(s) and desirable penetration-enhancing agents, contact
skin adhesive containing permeable self-adhesive or of a desirable penetration-enhancing agent
coating for these components or surrounding Matrix layer(s), a removable protective layer, or

b) a covering provided with a contact adhesive containing desirable penetration-enhancing
agents,

1 to 3 (at times) leaving uncovered contact adhesive edges, fastened to the contact adhesive by
means of a cover, of 1 or more ester(s) of

1 3-ethyl- 1 7?-hydroxy- 1 1 -methylene- 18,1 9-dinor- 1 7?-pregn-4-ene-20-yne-3 -one

matrix layer(s) containing optionally 1 or more estrogens and penetration-enhancing agents and a

removable protective layer, or

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

21 5-772- 1820/fax 215-772-182

wo 97/03709

PCT/EP96/03033

c) an impermeable cover layer,

1 to 3 present on or in the protective layer, of 1 or more esters of
1 3 -ethyl- 1 7?-hydroxy- 1 1 -methylene- 18,1 9-dinor- 1 7?-pregn-4-ene-20-yne-3 -one,
medicine reservoir(s) containing optionally one or more estrogens and desirable
penetration-enhancing agents,

1 to 3 skin contact adhesive layer containing permeable polymer layer(s) of a permeable
optional penetration-enhancing agent for these components and a removable protective layer.

A transdermal therapeutic system according to variant a) describes a simple matrix system. It
can be, by way of example, in a circular, oval or rectangular shape and be prepared as follows.

A solution or suspension of up to 40% by wt. of active material or active material mixture,
0-40% by wt. of a penetration enhancing agent, 30-70% by wt. of a customary medical adhesive
filled with a suitably volatile solution to 100% by wt. is stretched into a flat impermeable
adhesive layer. After drying, a second and even later possibly a third optional active material,
penetration enhancing agent and adhesive containing layer can be attached to this layer and
dried. Then the matrix system is provided with a removal protective layer.

One uses a customary medicine matrix constituent which after drying of the system does not or
does not sufficiently adhere to the skin, so one can cover or enclose the system by raising the
removable protection layer even more with a skin contact adhesive.

Suitable solvents and penetration enhancing agents, by way of example, possess the already
mentioned fluidity of this type. Suitable as customary medicinal adhesives are, by way of
example, polyacrylates, silicons, polyurethanes, blockpolymers, styrol-butadiene-copolymers as
well as natural or synthetic rubbers, such as for example polyisobutylenes. Cellulose ethers,
polyvinyl compounds or silicates are under consideration as additional matrix structures. For
increasing the adhesiveness of the receiving matrix the customary additives could be added such
as, for example, glutinous producing rosins and oils. Above and beyond that crystallization
inhibitors could be added such as, for example Kollidon® VA 64 for increasing the

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street -

21 5-772- 1820/fax 215-772-182

Suite 1407, Philadelphia, PA USA

wo 97/03709

PCT/EP96/03033

physical stability of the systems as described, by way of example, in WO 93/08797.

All foils are suitable as protection layers which are ordinarily used in therapeutic systems. Such
foils, by way of example, are siliconized or fluoropolymer layers.

By way of example, one can use 10 to 100 |im thick polyethylene or polyether foils, selectively
pigmented or metallized as cover layers in this system. The medicine layer raised hereupon is
preferably a thickness of 2 to 500 |im. The delivery of the active material is preferably over a
surface of 5 to 100cm 2.

In multi-layered matrix systems, by way of example, in which the matrix can be applied to the
impermeable adhesive layers in which are introduced 1 or more esters of 13-eth
yl-17?-hydroxy-l l-methylene-18,19-dinor-17?-pregn-4-ene-20-yne-3-one and optionally the
penetration enhancers while the layer or layers under it contain the estrogens and optionally even
penetration enhancers. Besides it is however also possible in such a transdermal system to
arrange several active material-containing matrices side by side.

A transdermal therapeutic matrix system according to variant b can, by way of example, also be
circular, oval or rectangular and be prepared as follows.

A covering is coated with a skin contact adhesive. Then 1 to 3 working areas with an
impermeable covering is/are pasted to this pro TTS to provide 1 or more ester(s) of
13-ethyl-17?-hydroxy-ll-methylene-18,19-dinor-17?-pregn-4-ene-20-yne-3-one, optionally 1 or
more estrogens and penetration enhancing agents containing matrix layers so that the covering of
a sufficient edge for attaching to the skin and in multiple areas sufficiently between spaces and it
is provided with a removable protective layer. The materials used in these matrix systems can be
the same as those mentioned in Variant a.

A transdermal therapeutic reservoir system according to Variant c, by way of example, can
likewise be circular, oval or rectangular and are described as follows:

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

2 1 5-772- 1 820/fax 2 1 5-772-1 82

wo 97/03709

PCT/EP96/03033

An impermeable foil is shaped by heat and/or tension so that one to three 0.1 to 3 ml bulging
shape is formed. This is filled with an active material containing solvent or suspension having 1
- 50% by wt. of active material or active material mixture with a penetration-enhancing agent.
The active material containing solution or suspension can also be thickened with up to 10% by
wt. of matrix builders.

A fused or pasted permeable polymer layer serves as the covering of the reservoir for the skin,
upon which a permeable skin contact adhesive layer and a removable protection layer are stuck.

The above-mentioned penetration-enhancing agents could be used in these systems. By way of
example, a 20 to 200 ?m thick foil of cellulose esters, cellulose ethers, silicones or polyolefin
compounds are used as permeable polymer layer. Through the variation in these polymer layers
the diffusion velocity of the active materials or active material mixtures vary within a wider
range.

The same materials are suitable as adhesives and protection layers which are described in the
transdermal therapeutic systems according to variant a.

hi the preparation of transdermal therapeutic systems with 2 or 3 arranged side-by-side active
material containing matrix layers or medicine reservoirs it is often suitable to introduce in one, 1
or more esters of

13-ethyl-17B-hydroxy-l l-methylene-18,19-dinor-17?-pregn-4-ene-20yne-3-one and in the other,
1 or more estrogen(s). hi the cases of this type the active material-containing matrix systems or
medicine reservoir containing not only different active materials but as well even additional,
different penetration enhancing agents.

In the case of the matrix systems according to variant a or b one must take care to have a
sufficient difference in the care area in order to stop any diffusion of active material at times into
the other area, hi the case of the reservoir systems according to variant c it is possible for
individual reservoirs to be provided with different permeable polymer layers so the diffusion
flow of the individual active materials at times meets the requirements.

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

2 1 5-772- 1 820/fax 2 1 5-772- 1 82

wo 97/03709

PCT/EP96/03033

Additional characteristics of the transdermal system according to the invention are explained on
the basis of the annexed , but not in correct scale drawings.

Fig. 1 shows a cross-section through a circular matrix system surface according to variant a
without the removable protective layer. It is composed of the impermeable cover layer 1 and the
medicine containing matrix layer 2.

Fig. 2 shows a cross-section through a matrix system surface according to variant b without the
removable protective layer. Fig. 3 shows the top view to these systems. The system consists of
the covering 3 that is provided with a contact adhesive layer 4. Two medicine containing matrix
layers 6 and 8 are affixed to these contact adhesive layers by means of the impermeable
coverings 5 and 7.

Fig. 4 shows a cross-section through a round, single-chamber reservoir system according to c
without the removable protective layer. It is composed of the impermeable layer 9, the medicine
reservoir 10, the permeable polymer layer 11 and the skin contact adhesive layer 17.

In addition, transdermal therapeutic systems are also suitable for further galenical preparations
for transdermal application of the esters of

1 3 -ethyl- 1 7B-hydroxy- 1 1 -methylene- 18,1 9-dinor- 1 7?-pregn-4-ene-20yne-3 -one.

An emulsion gel for transdermal applications consists of, by way of explanation, the active
material or active material mixture, penetration enhancing agents, emulsifiers (in which
ambiphile substituents of the penetration enhancing agents can serve as emulsifiers) and in such
a case matrix formers. A typical receptor consists of 0.1 - 25% by wt. of active material or
active material mixture, 0 - 10% by wt. of emulsifier, 0 - 5% by wt. of matrix former, 0 to 50%
by wt. penetration enhancing agents and water to 100% by wt. The agent is emulsified in the
usually manner and if necessary treated with the usual antioxidants, preservatives, etc.

Translated by Tex Translation & Interpreting Services * 1 5 1 8 Walnut Street - Suite 1407, Philadelphia, PA USA

21 5-772- 1820/fax 215-772-182

wo 97/03709

PCT/EP96/03033

Single-phase gels are obtained, by way of example, by dissolving or suspending the active
material or active material mixture in solvents such as water, and secondary alcohols or mixtures
of them, if necessary, addition of penetration-enhancing agents and thickening with matrix
formers.

Typical receptors for such gels containing 0.01 - 25% by wt. of active material or active material
mixture, 0 to 40% by wt. of penetration enhancing agent supplied with up to 100% solvent.

Also, the gels can contain, as desired, antioxidants, preservatives, etc.

A typical spray receptor, by way of example, is:

1 - 25% by wt. of active material or active material mixture, 0 - 20% by wt. of matrix former, 0 -
60% of penetration enhancing agent supplied with solvents and if necessary purgatives up to
100%. Pressure gas packs are used so the purgatives can escape.

The esters, according to the invention, of 13 -ethyl- 1713-hydroxy-l 1 -methylene- 18,
19-dinor-17?-pregn-4-ene-20-yne-3-one containing agents for transdermal application can be
used for treating similar illnesses, such as the previously known, by way of example, orally
administering agent containing highly active gestagens. Beyond that, if necessary, the estrogen
containing preparation can be found as well being used for contraceptives. The agents,
according to the invention, are especially advantageous in the treatment of illnesses that require a
long-term treatment with relatively high doses of the active material. Here, the application
frequency can be substantially reduced and a corresponding blood plasma tolerance gel be
substantially increased. A further advantage is that the gastrointestinal secondary effects are not
to be expected and the first liver passage is by-passed in estrogen containing preparation
combinations and that the doses can be reduced by estrogen.

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

2 1 5-772- 1 820/fax 2 1 5-772- 1 82

wo 97/03709

PCT/EP96/03033

These advantages allow the estrogen-free monotherapeutics of the previous invention to appear
as especially suitable to, by way of example, treat endometriosis, gestagen dependent tumors,
benign breast illnesses or premenstrual syndrome.

The transdermal use of estrogen in sequential or continuous combination with esters of
13-ethyl-17B-hydroxy-ll-methylene-18,19-dinor-17?-pregn-4-ene-20yne-3-one are especially
advantageous, by way of example, for treating climatic maladies, for preparation of
osteoporoses, cycle regulation and cycle stabilization.

The following explanatory examples serve to more clearly explain the invention. The following
commercial products are used in them:

0.074 mm thick polyester foil (Skotchpak® manufactured by 3M; polypropylene foil (Celgard®
2500) manufactured by Celanese, Liner foil Skotchpak® 1022 and 1360 manufactured by 3M;
Transfer Adhesive 9871 manufactured by 3M, Sichello® type J 6610-21 polyacrylic ester -
adhesive manufactured by Henkel KG, Oppanol® type B15SF poly-isobutylene - adhesive
manufactured by BASF, Monsanto Gelva® polyacrylate ester - adhesive, X-7-4502 type silicon
adhesive material manufactured by Dow Coming and HXF Klucel® type hydroxypropyl
cellulose manufactured by Hercules and KoUidon® 12PF as well as KoUidon® VA64
crystallization inhibitors manufactured by BASF.

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

215-772-1820/fax 215-772-182

wo 97/03709

PCT/EP96/03033

A: Agent for transdermal application

Example 1

While stirring, one after the other 0.8 g of

13-ethyl-17fi-hydroxy-ll-methylene-18,19-dinor-17?-pregn-4-ene-20yne-3-one and 8.0 g of
dimethyl isosorbit are introduced into 62.4 g of a 50% solution of silicon adhesive material in
benzene. After degassing the preparation, the mixture is laid out on a polyester film by means of
a coating device in such a way that after the removal of the volatile solvents a similar film of 40
g/m^ of solid coating forms. Connection is covered with a fluoropolymeric layer polyester liner.

The thus contained laminate is divided into 10 cm^ area individual circular plasters by means of
a stamping device and packed in aluminum foil. Fig. 1 shows a cross-section through this plaster
without the polyester-liner. The plaster adheres to the skin after removal of the liner foil.

The content determination is a similar active material proportion in the agent of 0.08 mg/m^.
Example 2

While stirring, 1 3 -ethyl- 1 7fi-hydroxy- 1 1 -methylene- 18,1 9-dinor- 1 7?-pregn-4-ene-20yne-3 -one
are introduced into 80 g of a 50% solution of polyacrylic acid ester in ethyl acetate (g:g) and
prepared as described in Example 1 .

The content determination is a similar active material proportion in the agent of 8 mg/m^.
Example 3

While stirring, 5.0 g of 13-ethyl-17B-hydroxy-l 1 -methylene- 18, 19

-dinor-17?-pregn-4-ene-20yne-3-one and 10.0 g isopropylmyristate are dissolved in 170 g of a
50% solution of polyisobutylene adhesive substance in acetone/benzene. After degassing the
preparation, the solvent is drawn onto the polyester film by means of a coating device in such a
way that after

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

215-772-1820/fax 215-772-182

WO 97/03709

PCT/EP96/03033

the removal of the volatile solvent, a similar film of 100 g/m^of solid coating formed.
Connection is covered with a fluoropolymeric layer polyester liner. The thus contained laminate

is divided into 10 cm^ area individual plasters by means of a stamping device and packed in
aluminum foil. After the removal of the liner foil the plaster adheres to the skin.

The content of 13 -ethyl- 17fi-hydroxy-l 1 -methylene- 1 8, 19-dinor-17?-pregn-4-ene-20yne-3-one
in the agent is 0.5 mg/cm^.

Example 4

While stirring, one after the other, 3. 5 g of estradiol, 3.5 g of

1 3 -ethyl- 17B-hexanoyloxy- 11 -methylene- 18, 19-dinor-17?-pregn-4-ene-20yne-3-one and 7.0 g
isopropylmyristate are dissolved or suspended in 1 12 g of a 50% solution of polyacrylester
adhesive substance in acetone/benzene. After degassing the preparation, the mixture is drawn out
onto the polyester film by means of a coating device in such a way that after the removal of the
volatile solvent, a similar film of 70 g/m^of solid coating formed. Connection is covered with a

siliconizing active material-fi'ee liner film. The thus contained laminate is divided into 5 cm^
area individual plasters by means of a stamping device and packed in aluminum foil. After the
removal of the liner foil the plaster adheres to the skin.

The content of 13-ethyl-17fi-hydroxy-l l-methylene-18,19-dinor-17?-pregn-4-ene-20yne-3-one
in the agent is 0.5 mg/cm^.

Example 5

Analogous to Example 1 are two different segment-like Matrix systems prepared that have the
profiles illustrated in Fig. 2 and Fig. 3. The matrix I consists of the matrix 8 provided with a
polyester foil 7 of the following composition 1 .0 mg of 17B-acetoxy-

13-ethyl-l l-methylene-18,19-dinor-17?-pregn-4-ene-20yne-3-one, 5.0 mg isopropylmyristate,
34 mg of acrylate contact adhesive material and 10 mg of Kollidon® VA64 and had a surface
area of 5 cm^.

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

215-772-1820/fax 215-772-182

wo 97/03709

PCT/EP96/03033

The matrix II consists of the matrix 6 provided with a polyester foil 5 of the following
composition 2.0 mg of estradiol, 10.0 mg isopropylmyristate, 68 mg of acrylate contact adhesive
material and 20 mg of Kollidon® VA64 and has a surface area of 10 cm^.

Example 6

A 7.4 cm diameter polyester foil is shaped by means of tension and heat such that a circular
bulge with a surface area of 10 cm^ is formed. This is filled with 1 ml of a solution of 2.5 mg
17B-butyryloxy- 13-ethyl-ll-methylene-18,19-dinor-17?-pregn-4-ene-20yne-3-one in
dimethylisosorbit. A polypropylene or cellulose acetate butyrate foil is fused to the edge.
According to the pressure per unit of time the sealing temperature is between 70°C and 100°C.
The contact adhesive foil is transferred onto the permeable polymer layer. The plaster is
provided with a liner and packed in aluminum foil.

Fig. 4 shows a cross-section through a plaster of this type without a liner.
Example 7

Analogous to Example 6 a polyester foil is shaped so that two half-circle shapes by means of a
gate from one to the other, forms separate bulges with surface areas of 7.5 cm^ each.

Reservoir I is filled with 0.75 ml of a suspension with 1 .5 mg of

1 7B-acetoxy- 1 3 -ethyl- 1 1 -methylene- 18,1 9-dinor- 1 7?-pregn-4-ene-20yne-3-one in

1 ,2-propandiol and Reservoir II with 0.75 ml of one such with 3.5 mg of estradiol in 1,

2-propandiol. The additional finishing of the plasters follows as described in Example 5.

Figure 5 shows a cross-section through a plaster of the type without liner.

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

215-772-1820/fax 215-772-182

• i

wo 97/03709

PCT/EP96/03033

Example 8

0.2 g of estradiol, 0.02 g 17B-butyryloxy- 13-ethyl-ll-methylene-18,19-dinor
-17?-pregn-4-ene-20yne-3-one, 10.0 g of 1 ,2-propandiol and 10.0 g isopropylmyristate, one after
the other is dissolved in 76.78 g of ethanol (96% by vol.) or isopropanol. Then 3 g of
hydroxypropyl cellulose solvent is added and the air degassed from it. After 2 hours the gel is
emptied into aluminum tubes with triple inner protection lacquering.

The analysis reveals a homogeneous active material portion in the gel with values of 95% to
105% of the theoretical values.

Examples 9

20.00 g of 13-ethyl-176-hexanoyloxy-l 1 -methylene- 1 8, 19-dinor-17?-pregn-4-ene-20yne-3 -one
are dissolved in 1000 g of isopropylmyristate, sterilized by filtration and emptied under aseptic
conditions into a 5 ml medicine bottle.

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

21 5-772- 1820/fax 215-772-182

WO 97/03709

PCT/EP96/03033

B: Syntheses

Example 1

5 g of 13-ethyl-17B-hydroxy-l l-methylene-18,19-dinor-17?"pregn-4-ene-20yne-3-one are
suspended in 34.5 ml (150 mmol) hexanoic acid anhydride, mixed with 1.04 g
N,N-dimethylaminopyridine and stirred for an hour at 0°C and another 8 hours at 20°C. Then
the mixture is chilled again at O^C, mixed with 2.0 g calcium carbonate and 12.5 ml of methanol,
stirred for 3 hours and mixed with 10 ml of water. The mixture is extracted with ethyl acetate,
then acetate-extract washed, then dried over sodium sulfate and degassed under vacuum. The
residue is examined chromatographically over a silica gel prism with 100:0 to 80:20
hexane-ethyl acetate and 5.85 g of 13-ethyl-176-hexanoylo

xy-1 l-methylene-18,19-dinor-17?-pregn-4-ene-20yne-3-one obtained with a melting point of
123-124°C .

Example 2

Under the conditions of Example 1, but using acetic anhydride,

17B-acetyl-13-ethyl-l l-methylene-18,19-dinor-17?-pregn-4-ene-20yne-3-one with a melting
point of 170-171 ""C is produced.

Example 3

Under the conditions of Example 1, but using butyric acid anhydride,

17B-butyryloxy- 13 -ethyl- 1 1 -methylene- 1 8, 19-dinor-17?-pregn-4-ene-20yne-3-one with a

melting point of 1 18-1 19°C is produced.

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

215-772-1820/fax 215-772-182

wo 97/03709

PCT/EP96/03033

Patent Claims

1 . Agent for transdermal application, characterized in that it contains one to three esters of
13-ethyl-17B-hydroxy-l 1 -methylene- 1 8, 19-dinor-17?-pregn-4-ene-20yne-3 -one with 1 to
20 carbon atoms in the ester group optionally in combination with

1 3-ethyl- 1 7B-hydroxy- 1 1 -methylene- 18,1 9-dinor- 1 7?-pregn-4-ene-20yne-3 -one and/or
with 1 to 3 estrogens.

2. Agent for transdermal application according to Patent Claim 1, characterized in that it
contains an ester of 1 3 -ethyl- 1 7B-hydroxy- 1 1 -methylene- 18,

1 9-dinor- 17?-pregn-4-ene-20yne-3-one with 2 to 12 carbon atoms in the ester group.

3. Agent for transdermal application according to Patent Claims 1 and 2, characterized in
that it contains 1 ester of

1 3 -ethyl- 1 7B-hydroxy- 1 1 -methylene- 18,1 9-dinor- 17?-pregn-4-ene-20yne-3 -one with 2 to
8 carbon atoms in the alkanoyl group.

4. Agent for transdermal application according to Patent Claims 1 to 3, characterized in that
estradiol, estriol, 17?-ethinylestradiol, mestranol, 14?,17?-ethanoestra-l,3,5(10)-triene-3,
17?-diol, 14?,17?-ethanoestra-l,3,5(10)-triene-3,16?, 17B-triol, mestranol or
combinations of these esters are used as estrogen(s).

5. Agent for transdermal application according to Patent Claims 1 to 4, characterized in that
the agent is a transdermal therapeutic system (TTS),

6. Agent for transdermal application according to Patent Claim 5, characterized in that the
transdermal therapeutic system is composed of:

a) an impermeable covering layer,

1 to 3 pasted onto the covering layer, of 1 or more ester(s) of 13 -ethyl
- 1 7?-hydroxy- 1 1 -methylene- 1 8, 1 9-dinor- 1 7?-pregn-4-ene-20-yne-3-one containing
optionally 1 or more estrogen(s) and desirable penetration-enhancing agents, contact skin
adhesive containing permeable self-adhesive or of a desirable penetration-enhancing age
nt coating for these

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

21 5-772- 1820/fax 215-772-182

wo 97/03709

PCT/EP96/03033

components or surrounding Matrix layer(s), a removable protective layer, or

b) a covering provided with a contact adhesive containing desirable
penetration-enhancing agents,

1 to 3 (at times) leaving uncovered contact adhesive edges, fastened to the contact
adhesive by means of a cover, of 1 or more ester(s) of

1 3 -ethyl- 1 7?-hydroxy- 1 1 -methylene- 18,1 9-dinor- 1 7?-pregn-4-ene-20-yne-3 -one matrix
layer(s) containing optionally 1 or more estrogens and penetration-enhancing agents and
a removable protective layer, or

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

215-772-1820/fax 215-772-182

' If

wo 97/03709

PCT/EP96/03033

c) an impermeable cover layer,

1 to 3 present on or in the protective layer, of 1 or more esters of
1 3 -ethyl- 1 7?-hydroxy- 1 1 -methylene- 18,1 9-dinor- 1 7?-pregn-4-ene-20-3Tie-3 -one,
medicine reservoir(s) containing optionally one or more estrogens and desirable
penetration-enhancing agents,

1 to 3 skin contact adhesive layer containing permeable polymer layer(s) of a permeable
optional penetration-enhancing agent for these components and a removable protective
layer.

7. Agent for transdermal application according to Patent Claim 6, characterized in that it
contains an active material ladened matrix layer or a medicine reservoir.

8. Agent for transdermal application according to Patent Claim 6, characterized in that it
contains 2 or 3 active material ladened matrix layers or a medicine reservoir.

9. Agent for transdermal application according to Patent Claim 8, characterized in that it
contains active material ladened matrix layers or the medicine reservoir of different
active materials.

1 0. Use of esters of 1 3 -ethyl- 1 7fi-hydroxy- 1 1 -methyle
ne-18,19-dinor-17?-pregn-4-ene-20-yne-3-one with 1 to 20 carbon atoms in the ester
group optionally in combination with one or more estrogen(s) for producing the
transdermal agent with active material or mixture of active materials.

1 1 . Use of esters of
13-ethyl-17B-hydroxy-ll-methylene-18,19-dinor-17?-pregn-4-ene-20-yne-3-one with 1
to 20 carbon atoms in the ester group in combination with one or more estrogen(s) for
producing an agent according to Patent Claim 10, characterized in that estradiol, estriol,
17?-ethinylestradiol, mestranol, 14?,17?-ethanoestra-l,3,5(10)-triene-3?, 17?-diol,
14?,17?-ethanoestra-l,3,5(10)-triene-3?,16?,17?-triol, or combinations of these esters are
used as estrogen(s).

Translated by Tex Translation & Interpreting Services * 1518 Walnut Street - Suite 1407, Philadelphia, PA USA

215-772-1820/fax 215-772-182

wo 97/03709

PCT/EP96/03033

12. Use of esters of

13 -ethyl- 17B-hydroxy-l l-methylene-18,19-dinor-17?-pregn-4-ene-20-yne-3-one with 1
to 20 carbon atoms in the ester group in combination with one or more estrogen(s) for
producing an agent according to Patent Claim 1 1 and 12, characterized in that the agent is
a transdermal therapeutic system (TTS).

13. Use of esters of

13 -ethyl- 17B-hydroxy-l l-methylene-185l9-dinor-17?-pregn-4-ene-20-yne-3-one with 1
to 20 carbon atoms in the ester group in combination with one or more estrogen(s) for
producing an agent according to Patent Claim 12, characterized in that it is a transdermal
therapeutic system according to Patent Claims 6 to 9.

14. Use of estrogen-free agents for transdermal applications according to Patent Claims 1 to
9 for transdermal contraception, treating of endometriosis, treating of gestagenic
abhangiger tumors and treating premenstrual syndromes.

15. Use of transdermal application agents according to Patent Claims 1 to 9 optionally in
combination estrogen -containing agents for treatment of climactic conditions, for
prevention of osteoporosis, cyclic regulation, for cyclic stabilization and transdermal
contraception.

16. Ester of 13-ethyl-176-hydroxy-l l-methylene-18,19-dinor-17?-pregn-4-ene-20yne-3-one
with 2 to 8 carbon atoms in the alkanoyl group.

17. 1 7?- Acetoxy- 1 3-ethyl- 1 1 -methylene- 18,1 9-dinor- 1 7?-pregn-4-ene-20yne-3 -one

1 8. 17?-Butyryoxy-13-ethyM l-methylene-18,19-dinor-17?-pregn-4-ene-20yne-3-one

19. 1 3-Ethyl- 1 7?-hexanoyloxy- 1 1 -methylene- 18,1 9-dinor- 1 7?-pregn-4-ene-20yne-3 -one

Translated by Tex Translation & Interpreting Services * 1 5 1 8 Walnut Street - Suite 1407, Philadelphia, PA USA

215-772-1820/fax 215-772-182

Internet Archive Audio

Featured

Top

Images

Featured

Top

Software

Featured

Top

Books

Featured

Top

Video

Featured

Top

Mobile Apps

Browser Extensions

Archive-It Subscription

Save Page Now

Full text of "USPTO Patents Application 09634399"

See other formats